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Enhancement of Mucosal Immune Responses in Chickens by Oral Administration of Cysteamine¹

Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture, Nanjing Agricultural University, Nanjing, 210095, China

² Corresponding author: zxbyq{at}njau.edu.cn

	ABSTRACT

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Somatostatin, a tetradecapeptide originally isolated from the hypothalamus, can exert an inhibitory effect on the secretion of growth hormone by the anterior pituitary gland. In addition to endocrine organs, somatostatin is also present in the digestive tract and immune organs. In lymphoid tissues, somatostatin appears to play a role in the modulation of the immune response. Cysteamine (CS) is a sulfhydryl reducing agent that is known as a depletory agent of somatostatin. To evaluate its effects on chicken mucosal immune responses, CS was administrated orally to 1-wk-old broilers (40 mg/kg) that were immunized orally with Newcastle disease attenuated vaccine (NDV). The number of IgA-positive cells and intestinal intraepithelial lymphocytes (iIEL) in duodenum and jejunum were examined at 3-, 5-, and 7-wk posttreatment and immunization. The number of somatostatin-positive cells and relative amounts of somatostatin mRNA were also examined in the duodenum. The number of somatostatin-positive cells in the duodenum was reduced (P < 0.05) after CS treatment. In broilers receiving CS and NDV treatment (CS+NDV) the level of IgA-positive cells and iIEL in the duodenum and jejunum was increased (P < 0.05) at 3 and 5 wk posttreatment. The expression of somatostatin mRNA increased (P < 0.05) compared with that of the control group at 5 wk after immunization in broilers receiving CS+NDV or NDV alone. The results suggest that CS can induce proliferation and differentiation of IgA-positive cells and iIEL in the intestinal mucosa of chickens by reducing the number of somatostatin-positive cells.

Key Words: cysteamine • mucosal immunity • immunoglobulin A-positive cell • intestinal intraepithelial lymphocyte • somatostatin-positive cell

	INTRODUCTION

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Oral immunization has received much attention in vaccine development because of its easy and safe administration. However, large and repeated antigen doses are often required to achieve a protective immune response because of degradation of the antigen by gastric acid and proteases present in the gastrointestinal tract. There is therefore a great need to overcome this problem by developing strategies for enhancing delivery of antigen to the mucosal immune system and identifying mucosa-active immunostimulating agents (adjuvants; Holmgren et al., 1992).

The intestine contains functionally distinguishable populations of immune cells and neuropeptide-secreting cells, which provide the anatomical basis for research on neuroimmune interactions (Ottaway, 1991; Genton and Kudsk, 2003). The neuropeptide somatostatin is widely present in the gastrointestinal system of many animals (Reichlin, 1983; McIntosh, 1985; Miyamoto and Miyamoto, 2004). It recently has been demonstrated that somatostatin can modulate lymphocyte function. Somatostatin and somatostatin receptors are expressed in lymphoid organs, and somatostatin has been shown to exert inhibitory effects on the immune response (Stanisz et al., 1986; Fais et al., 1991; Bokum et al., 2000; Ferone et al., 2001), especially on the synthesis of immunoglobulins and cytokines (Aguila et al., 1991; Van Hagen, 1996).

Cysteamine (CS) is reported to deplete immunoreactive somatostatin in the central nervous system and the gastrointestinal tract of animals (Szabo and Reichlin, 1981; Millard et al., 1985). Considering the inhibitory effects of somatostatin on several aspects of immune function, we hypothesized that CS will enhance the immune response in the local mucosal tissue by depleting somatostatin in the intestine. The present study was designed to investigate effects of CS on aspects of the mucosal immune response and on somatostatin levels in chickens following immunization with attenuated Newcastle disease virus (NDV).

	MATERIALS AND METHODS

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Experimental Design

Seven-day-old broilers (Arbor Acres Farm Inc., Nanjing, China) were obtained from the animal facility at Nanjing Agricultural University and reared in isolation. Eighty-four animals were divided into 4 groups of 21 broilers each: control, CS, NDV, and NDV+CS. Broilers in the CS group were orally given a 5% CS solution at a dose of 40 mg/kg of BW. The 5% CS solution (wt/vol) was prepared in Hank’s balanced salt solution and delivered orally to animals with a syringe. Birds in the NDV group were orally vaccinated with a dose of 10⁶ (50% egg infective dose) of NDV. Broilers in the NDV+CS group were given CS and 4 h later vaccinated with NDV as described above. Vaccination with NDV and CS was repeated 3 d later. Broilers assigned to the control group orally received Hank’s balanced salt solution instead of CS.

Collection of Samples

Animals were decapitated on wk 3, 5, and 7 after the first vaccination (posttreatment, PT). Samples (duodenum, jejunum, and serum) were collected from 6 chickens in each group. Serum was collected from the clotted blood obtained from the wing vein and centrifuged at 2,000 x g for 5 min. Tissue samples of duodenum and jejunum (3 pieces of each tissue taken 1 cm away from each other) were frozen in liquid nitrogen immediately, then stored at – 80 ° C until RNA extraction and other analysis. Other tissue samples of duodenum and jejunum (at least 3 pieces, 1 cm away from each other) were fixed in 10% neutral buffered paraformaldehyde for 24 h for routine histology.

Tissue Preparation for Histological Examination of Intraepithelial Lymphocytes

Paraffin-embedded, fixed, and processed duodenum and jejunum samples were cut into 5-µm semiserial cross sections. Per tissue sample, 20 sections at least 50 µm apart were prepared, stained with hematoxylineosin stain, and covered with coverslips.

Immunohistochemical Staining for IgA-Positive Cells

Frozen tissues sections (16 µm) of duodenum and jejunum were placed on polylysine coated glass slides and fixed in 4% paraformaldehyde in borate buffer (0.01 M, pH 11). Twenty sections at least 100 µm apart were prepared per sample. Endogenous peroxidase activity was inhibited by preincubating the tissues in 3% H₂O₂. The sections were then incubated in 5% normal goat serum for 0.5 h followed by an overnight incubation at 4 ° C with 1:40 dilution of rabbit antichicken IgA serum (Yang and Mao, 2003) in PBS containing 0.02% Triton X-100 and 0.01% bovine serum albumin. After rinsing in PBS, sections were incubated with biotinylated goat antirabbit IgG (1:300, Vektor ABC kit, PK-6101) for 1 h at room temperature, followed by incubation with an avidinbiotin-peroxidase conjugate solution for 1 h at room temperature. The sections were then rinsed 3 times with PBS and incubated with 3,3'-diaminobenzidin tetrahydrochloride (Sigma) solution dissolved in 0.05 M Tris-HCl buffer (pH 7.4) at room temperature. Ten minutes later the enzyme-substrate reaction was stopped with 0.05 M Tris-HCl buffer (pH 7.4). Sections were then rinsed in PBS and counterstained with methyl green stain. At last, sections were cleared and sealed with a glass coverslip.

Immunohistochemical Staining for Somatostatin-Positive Cells

Frozen sections of duodenum and jejunum were serially cut at 16-µm thickness and fixed with 4% paraformaldehyde in borate buffer (0.01 M, pH 11). Endogenous peroxidase activity was inhibited by preincubation with 3% H2O2. Sections were then incubated in 5% normal goat serum for 0.5 h, followed by incubation with a 1:4,300 solution of rabbit antisomatostatin serum (Incstar, Stillwater, MN) in PBS containing 0.02% Triton X-100 and 0.01% bovine serum albumin for 72 h at 4 ° C. After rinsing in PBS, sections were subsequently incubated in goat antirabbit biotinylated IgG diluted 1:300 (Vector ABC kit, PK-6101) for 1 h at room temperature, followed by incubation with avidinbiotin-peroxidase conjugate solution for 1 h at room temperature. After rinsing with PBS, sections were exposed to 3,3'-diaminobenzidin tetrahydrochloride (Sigma) solution at room temperature for 15 min. The reaction was stopped with 0.175 M sodium acetate buffer (pH 6.0). Sections were then rinsed in PBS and counterstained with methyl green stain. Finally, sections were cleared and sealed with a glass coverslip.

Analysis of Tissue Sections

To determine the number of intraepithelial lymphocytes (iIEL), tissue sections were examined using the 40 x stage objective of an Olympus BX50 bright-field microscope. For each tissue section (20 section per sample), iIEL in 5 microscope fields (10 villi per field) were counted and data expressed as the average number of iIEL per villus. For immunohistochemically stained sections, the area occupied by cells of interest (IgA-positive or somatostatin-positive cells) in the lamina propria was determined per microscope field using an image analysis system (VIDS Synoptics Version 4.5.0.29 [EC] , Cambridge, UK). For these analyses, 5 microscope fields per section and 5 sections per tissue sample were examined. The level of somatostatin-positive cells was only assessed for the duodenum because somatostatin is primarily detected in the upper part of the small intestines. Data were expressed as the relative area occupied by stained cells.

Semiquantitative Reverse Transcription-PCR for the Detection of Somatostatin mRNA

Total RNA was extracted from the duodenum using g uanidinium thiocyanate-phenol-chloroform 1-step method. The RNA was transcribed into cDNA with random hexamer primers. A reverse transcription (RT) control tube containing all RT reagents except reverse transcriptase was included to monitor genomic DNA contamination.

Somatostatin primers were designed according to the chicken genomic DNA sequence (GenBank Accession No. U36385), forward primer: 5'-tcagagccaagccag aca-3' and reverse primer: 5'-ggaggacaggtgggtttca-3' . The ß-actin mRNA internal standard was designed using Primer Premier 5.0 (Premier Biosoft International, Palo Alto, CA) and synthesized by Haojia Biotech. The PCR reaction mixture contained 5 µL of 10 x PCR buffer, 1.5 mmol/L MgC₂, 0.2 mmol/L deoxyribonucleoside triphosphate, 100 ng of somatostatin forward and reverse primer, 2 µL of ß-actin primer pair, 2 µL of RT product, 1.0 U of Taq DNA polymerase in a total volume of 50 µL. Amplification conditions included initial denaturation 94 ° C for 5 min, 32 cycles of denaturation at 94 ° C for 30 s, annealing at 55 ° C for 30 s, extension at 72 ° C for 1 min, and a final extension step at 72 ° C for 5 min. All samples were amplified in the same PCR run with quality and contamination controls using a GeneAmp PCR System 9600 (Perkin Elmer, Waltham, MA). Twenty microliters of the PCR products were separated through 2.0% agarose gel electrophoresis. The band intensity was analyzed with Kodak 1D electrophoresis documentation and analysis system 120 (Kodak Photo Film Co. Ltd., Rochester, NY). The ratio of somatostatin to ß-actin mRNA intensity was used to determine the relative abundance of somatostatin mRNA expression.

Statistical Analyses

For each aspect examined, the Student t-test was applied to measure the statistical difference between group means at a sampling time (3, 5, and 7 wk PT). Means were considered different at P < 0.05).

	RESULTS

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Effects of Cysteamine on the Number of iIEL

The histological results showed that intestinal iIEL were localized between the cells of luminal epithelium layer and also in the basal region of the epithelium in the duodenum and jejunum (Figure 1, panel A). For both tissues, the number of iIEL was not different between treatment groups at 3 and 7 wk PT (Figure 2, panels A and B). At 5 wk PT, there were more (P < 0.05) duodenal iIEL in broilers from the CS and the NDV+CS groups compared with the control group (Figure 2A). The iIEL numbers in broilers from the NDV group were between those of the CS and NDV+CS groups and the control group. Similarly, at 5 wk PT, the number of jejunal iIEL was higher (P < 0.05) in broilers from the CS, NDV, and NDV+CS treatment groups than in broilers from the control group (Figure 2, panel B).

View larger version (56K): [in this window] [in a new window]   Figure 1. The distribution of intestinal intraepithelial lymphocytes (iIEL), IgA-positive cells, and somatostatin-positive cells in the duodenum of broilers. A. Hematoxylin and eosin stained section showing iIEL (viewed at 600 x magnification); B. and C. Immunohistochemically stained IgA-positive cells in the duodenum (viewed at 200 x ). D. Immunohistochemically stained somatostatin-positive cells in the duodenum (viewed at 200 x ).

View larger version (36K): [in this window] [in a new window]   Figure 2. Effects of cysteamine on the number of intestinal intraepithelial lymphocytes (iIEL) and on the relative levels of IgA-positive cells, somatostatin-positive cells and somatostatin mRNA at 3-, 5-, and 7-wk posttreatment with cysteamine (CS), Newcastle disease attenuated vaccine (NDV), or both. One-week-old broilers were given an oral administration of the vehicle (control), CS (40 mg/kg), NDV, or CS and 4 h later NDV. The NDV administration was repeated 3 d later. Duodenum and jenunum were collected for conventional histology (iIEL), immunohistochemical staining (IgA-positive and somatostatin-postive cells), and mRNA isolation at 3-, 5-, and 7-wk postinitial treatment from 6 birds per treatment group. A and B. Mean number of iIEL per villus ± SD in the duodenum (A) and the jejunum (B). C and D. Relative levels of IgA-positive cells determined by image analysis. Mean area ± SD occupied by IgA-positive cells in the duodenum (C) and jejunum (D). E. Relative levels of somatostatin-positive cells (mean area ± SD). F. Levels of somatostatin (SS) mRNA relative to ß-actin mRNA expression (mean area ± SD). a–cWithin a sampling week, means without a common letter are different at P < 0.05.

In the duodenum, IgA-positive lymphocytes were identified by their characteristic morphology: round, with a nucleus surrounded by a ring of yellow-brown stain. These cells were present in the lamina propria of villi in the duodenum and jejunum (Figure 1, panels B and C). As shown in Figure 2, panel C, at 3 and 5 wk PT there were more IgA-positive cells in the duodenum in the NDV+CS group (P < 0.05) compared with the control, CS, and NDV groups. Broilers in the CS and NDV treatment groups tended to have higher levels of duodenal IgA-positive cells than broilers in the control group. This trend was significant at 5 wk PT (P < 0.05). At 7 wk PT, all groups of broilers had similar levels of duodenal IgA-positive cells (Figure 2, panel C). In the jejunum, treatment effects were only observed at 3 wk PT, when broilers from the NDV+CS group had higher (P < 0.05) levels of IgA-positive cells than broilers from the other 3 groups (Figure 2, panel D).

Effects of Cysteamine on the Somatostatin-Positive Cells in the Duodenum

The distribution and change of somatostatin-positive cells were studied by immunohistochemical technique and image analysis in duodenal tissues. Somatostatin-positive cells in the duodenum were mainly distributed around intestinal glands and between the epithelial cells (Figure 1, panel D). At 3 and 5 wk PT, CS treatment, with and without NDV, significantly reduced the levels of somatostatin-positive cells compared with controls. In broilers receiving NDV treatment alone, the level of somatostatin-positive cells was higher than those of the controls (Figure 2, panel E). These treatment effects were more pronounced at 3 wk PT compared with 5 wk PT (P < 0.01 vs. P < 0.05, respectively). At 7 wk PT there were no group differences in the level of somatostatin-positive cells.

Effects of Cysteamine on the Relative Expression of Somatostatin mRNA in the Duodenum

The RT-PCR assay was used to examine the expression of somatostatin mRNA relative to ß-actin expression in the duodenum (Figure 3). At 5 wk PT, the relative expression of somatostatin mRNA in the duodenum was higher (P < 0.05) in broilers from the NDV and NDV+CS groups compared with broilers from the control group (Figure 2, panel F). In broilers treated with CS alone, the relative expression of somatostatin mRNA was between that of the NDV and NDV+CS treated groups and the control group. There were no group differences in the relative expression of somatostatin mRNA at 3 and 7 wk PT.

View larger version (20K): [in this window] [in a new window]   Figure 3. Example of agarose gel electrophoresis of ß-actin and somatostatin (SS) PCR products. The PCR products prepared from duodenal RNA isolated from broilers 5 wk after oral treatment with vehicle (control), Newcastle disease attenuated vaccine (NDV), cysteamine (CS, 40 mg/kg), or CS and NDV. The PCR products shown are ß-actin (top band) and SS (bottom band) for the NDV group (lane 1 and 2), CS group (lane 3 and 4), NDV+CS group (lane 5 and 6), and the control group (lane 7 and 8).

	DISCUSSION

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Previous studies have been shown that somatostatin exerts widely inhibitory effects on the immunological response (Stanisz et al., 1986; Aguila et al., 1991; Fais et al., 1991; Van Hagen, 1996). In particular, somatostatin exerts an immunosuppressive effect on lymphocytes of the intestine (Payan and Goetzl, 1985; Nio et al., 1993). Somatostatin was shown to decrease DNA synthesis (30 to 50%) in lymphocytes from Peyer’s patches (Stanisz et al., 1986), to markedly affect the secretion of proinflammatory cytokines from intestinal epithelial cells (Levite and Chowers, 2001) and to exert inhibitory effects on IL-2 production of T lymphocyte in vitro (Payan and Goetzl, 1985; Nio et al., 1993). Moreover, it appears that somatostatin predominantly affects IgA-positive B cells compared with other B cells (Srikant and Patel, 1984; Stanisz et al., 1986). Somatostatin levels at mucosal sites are 100- to 1,000-fold higher than in blood (Fais et al., 1991). Receptor analysis studies have been shown that somatostatin receptors are present on more than 80% of all lymphocytes from Peyer’s patches in mice, and the affinity of these somatostatin receptors on lamina propria lymphocytes in the intestinal mucosa is 1,000 times higher than that of somatostatin receptors present on peripheral blood lymphocytes (Fais et al., 1991). This suggests that somatostatin may have more specific effects on the gut-associated lymphoid tissue than on lymphocytes in other tissues.

Cysteamine, known as a depletory agent of somatostatin (Szabo and Reichlin, 1981; Srikant and Patel, 1984), has been included in husbandry protocols to promote animal growth in China (Schmidt et al., 1999; Jiang et al., 2002; Zhou et al., 2002). In the present study, we examined the use of CS as an immunostimulating agent based on its ability to deplete somatostatin, and hence reduce its immunoinhibitory effects, in the intestine. Our results showed that in the duodenal tissue of broilers the levels of somatostatin-positive cells, but not somatostatin mRNA levels, were reduced 3 and 5 wk post-CS treatment. Papachristou et al. (1994) reported that CS increased somatostatin mRNA by 2 h after administration. This initial increase in somatostatin gene expression was followed by a gradual reduction at 8 h (Papachristou et al., 1994). Considering the immediate effects of CS on somatostatin-gene expression, it is not surprising that this effect was no longer observed weeks after CS administration. The observed long-term effect of CS on the relative number of somatostatin-positive cells, which lasted more than 5 wk, appears to provide a sufficiently long inhibitory effect to avoid the negative immunomodulatory effects of somatostatin during the oral immune response to an antigen (e.g., NDV) administered during CS treatment. This is supported by the heightened relative numbers of IgA-positive cells in the intestines, especially the duodenum, at 3 and 5 wk PT in broilers receiving the NDV+CS treatment. Moreover, the increase in the number of iIEL at 5 wk in CS- and NDV+CS-treated broilers further suggests beneficial effects of CS treatment on mucosal immunity, especially considering that iIEL are a major source of cytokines such as IL-2, IL-5, and IFN- (Taguchi et al., 1991; Sim, 1995). By 7 wk PT, the level of somatostatin-positive cells, and presumably somatostatin levels, had returned to normal levels. Therefore we infer from this study that oral administration of CS can induce time-dependent alteration in somatostatin and somatostatin mRNA in intestinal tissues of broilers that favorably affect immune components within the gastrointestinal mucosa.

Disrupting the somatostatin concentration in the intestine by the administration of CS may also increase the concentration of growth hormone (GH; Millard et al., 1983). Growth hormone has been shown to exert stimulating effect on immune cells (Geffner, 1997). Hence, the positive effects of reduced somatostatin levels on the immune system may also be mediated indirectly via growth hormone.

This study has shown effects of oral CS administration on mucosal immune components that are indicative of improved mucosal immunity in broilers. More studies are needed to determine whether broilers treated with CS during immunization are better protected than broilers immunized without concomitant CS administration. Because CS is a physiological substance (2-aminoethathiol) formed primarily by degradation of coenzyme A, it promises to be a safe immunostimulating agent to improve mucosal immunity in chicks through depletion of somatostatin.

	FOOTNOTES

 
¹ This work was supported by grant 2004CB11750 from the National Basic Research Program of China and the Agricultural Science and Technology key task item of Jiangsu province, grant No. BE20004318.

Received for publication October 4, 2005. Accepted for publication March 22, 2007.

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This Article Abstract Full Text (PDF) Color Figures Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Yang, Q. Articles by Gong, X. Search for Related Content PubMed PubMed Citation Articles by Yang, Q. Articles by Gong, X.